CN1496358A - Process for preparation of citalopram - Google Patents
Process for preparation of citalopram Download PDFInfo
- Publication number
- CN1496358A CN1496358A CNA028061160A CN02806116A CN1496358A CN 1496358 A CN1496358 A CN 1496358A CN A028061160 A CNA028061160 A CN A028061160A CN 02806116 A CN02806116 A CN 02806116A CN 1496358 A CN1496358 A CN 1496358A
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- CN
- China
- Prior art keywords
- cyanide
- described method
- general formula
- citalopram
- organic bases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 title claims abstract description 25
- 229960001653 citalopram Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 150000007530 organic bases Chemical class 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052740 iodine Chemical group 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- ICAIHGOJRDCMHE-UHFFFAOYSA-O ammonium cyanide Chemical compound [NH4+].N#[C-] ICAIHGOJRDCMHE-UHFFFAOYSA-O 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000011630 iodine Chemical group 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical group [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 3
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- LVILGAOSPDLNRM-UHFFFAOYSA-N 4-methylpyrimidine Chemical compound CC1=CC=NC=N1 LVILGAOSPDLNRM-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000012954 diazonium Substances 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical class C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- -1 phenyl-(4 '-fluoro phenyl)-(3-dimethylaminopropyl) methyl Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- LVHBHZANLOWSRM-UHFFFAOYSA-N itaconic acid Chemical compound OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- KHEVPDFAQFJIGK-UHFFFAOYSA-N 2-sulfooxyethanesulfonic acid Chemical compound OS(=O)(=O)CCOS(O)(=O)=O KHEVPDFAQFJIGK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LZJDGVUMQGYLAH-UHFFFAOYSA-N C1(=O)OCC2=CC=CC=C12.[I] Chemical compound C1(=O)OCC2=CC=CC=C12.[I] LZJDGVUMQGYLAH-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- PEZHRHCLQDSVOR-UHFFFAOYSA-N FC1=CC=C(C=C1)C1(CC=CC(=C1)I)CCCN(C)C Chemical compound FC1=CC=C(C=C1)C1(CC=CC(=C1)I)CCCN(C)C PEZHRHCLQDSVOR-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical group O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to an improved and industrially advantageous process for the preparation of citalopram represented by the following Formula I, and pharmaceutically acceptable acid addition salt thereof.
Description
Invention field
The present invention relates to a kind of prepare citalopram shown in the following general formula I in industrial favourable improving one's methods, and citalopram is at the adduct of pharmaceutically acceptable acid.
General formula I
Background of invention
Citalopram is the anti-depressed medicine of knowing, and chemically is being known as 1-[3-(dimethylamino) propyl group]-1-(4-fluoro phenyl)-1,3-dihydro-5-isobenzofuran nitrile.It is that (5-hydroxyl-tryptamines, 5-HT) reuptake inhibithors, and in U.S. Patent No. 4,136 are mentioned in 193 for the first time for the thrombotonin of selectivity central role.As European patent No.474,580 is described, and citalopram also is used for the treatment of dementia and cerebrovascular disease.
In U.S. Patent No. 4,136, the method for preparing citalopram has been described in 193.Among the present invention, will
General formula I I
It is shown that 4-halogen-2-(methylol) phenyl-(4 '-fluoro phenyl)-(3-dimethylaminopropyl) methyl alcohol (wherein, X represents halogen) and the dewatering agent reaction, carry out closed loop and make 5-halo phthalal ether (5-halophthalane) derivative (wherein, X represents halogen) shown in the following general formula III.
General formula III
In inert organic solvents, compound shown in the general formula III and cuprous cyanide reaction make the citalopram shown in the general formula I.But, described method is not suitable for carrying out with technical scale, even this is because the permutoid reaction of 5-halo phthalal ether and cuprous cyanide refluxes in dimethyl formamide is spent the night and can not finish, therefore be difficult to the citalopram of gained is separated with corresponding 5-halogenated compound.
WO00/13648 has disclosed and has passed through the Cu of the halo of 5-shown in general formula III phthalal ether (wherein, X is bromine or iodine or corresponding triflate compound) at palladium catalyst and catalytic amount
+Or Zn
2+Existence down and cyanide source or in the presence of palladium catalyst and zinc cyanide react and prepare citalopram, and to separate corresponding 5-cyano group phthalal ether be citalopram.Described cyanide source is selected from potassium cyanide, sodium cyanide, ammonium cyanide and cyaniding tetra-allkylammonium.
In another PCT application, a kind of version of this method has been described among the WO00/11926, it is in the presence of nickel catalyzator, finishes the cyano group exchange with cyanide source.
Be subjected to following restriction in the method that is used to prepare citalopram described in the above-mentioned PCT application, and because a variety of causes of the following stated is not suitable for commercial applications.
-described palladium or the nickel composite of being reflected at exists down and carry out, and described palladium or nickel composite are very expensive, and be highly inflammable because they inconveniently operate on commercial size air and photaesthesia, is carcinogenic substance, and has limited commercial validity.
-because using, described method makes solvent as tetrahydrofuran (THF) and Anaesthetie Ether, described reaction conditions is dangerous and existence is exploded and the risk of fire.
Comprise in the other method described in the PCT application WO01/02383 5-halo phthalal ether derivant shown in the general formula III is changed into corresponding Grignard reagent, then by with comprise the compound that is connected to the cyano group on the leaving group and react and change into citalopram.Other method comprises from Grignard reagent and makes aldehyde, and changes it into cyano group by oxime or hydrazone intermediate.
Comprise many steps in the method described in the WO01/02383, and use non-commercially available raw material.
Therefore, above-described method all can not be entirely satisfactory on commercial size.
Summary of the invention
The objective of the invention is to solve the problem relevant, and be provided at the high efficiency method that improved cyano group exchange process prepares citalopram that passes through of viable commercial with prior art.Described method is simple, and with regard to simplicity economic and that operate on commercial size, provides various advantages.
More particularly, the present invention relates to prepare the method for citalopram shown in the general formula I,
General formula I
Described method is included in organic bases and exists down, makes general formula III in suitable solvent
General formula III
Shown 5-halo phthalal ether derivant (wherein, X is a bromine or iodine) and the cyanide source reaction, and separating corresponding 5-halo phthalal ether, i.e. citalopram shown in the general formula I is as free alkali or be its form at the adduct of pharmaceutically acceptable acid.
On the other hand, the present invention relates to the above-mentioned method for preparing the enantiomorph of S-shown in the general formula I.
Described cyanide source can be any source of cyanide ion donor that is.Preferred source is potassium cyanide, sodium cyanide, ammonium cyanide, cuprous cyanide, zinc cyanide, cyaniding tetra-allkylammonium or their mixture.The source that is more preferably is cuprous cyanide and zinc cyanide.Described cyanide source can use or excessive use with the chemical reaction equivalent.Should use the prussiate of 1-2 molar equivalent whenever the compound shown in the amount general formula III.
Term " suitable solvent " is meant any polar aprotic solvents.Suitable is that described solvent can be selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, N-methylpiperidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene (2H) pyrimidone (DMPU) or their mixture.
Suitable organic bases comprises that Trimethylamine, triethylamine, diisopropylamine, picoline, pyridine, pyridine derivate are as 2,6-lutidine, 4-methylpyrimidine, morpholine, morpholine derivative, quinoline, 1,8-diazonium two ring [5.4.0] 11 carbon-7-alkene (DBU), piperidines, aryl replace amine such as aniline and dicyclohexylamine or its mixture.Should use pyridine and quinoline.Described organic bases can use or excessive use with the chemical reaction equivalent.Should use the organic bases of 1-2 molar equivalent whenever raw material shown in the amount general formula III.
We think that the described nitrogen that comprises organic bases plays crucial effect, and help to finish reaction.It is believed that described alkali has formed the mixture shown in the general formula I V with described cyanide source under the situation of cuprous cyanide,
Alkali=the comprise nitrogen of organic bases
General formula I V
Described cyanide source is convenient to make nitrile and halogen exchange by transition state, and this relates to the coordination complex shown in the general formula V,
General formula V
Described reaction is usually at about 120-170 ℃, is preferably in 135-145 ℃ the temperature range to carry out.Describedly be reflected at about 3 hours and in some hrs, finish.
Intermediate shown in the general formula III (wherein, X is a bromine or iodine) can be prepared by the bromine or iodine phthalide respectively, and as U.S. Patent No. 4,136,193 is described, and described patent reference is incorporated in this.
Citalopram shown in the general formula I can be used as free alkali and obtains, and perhaps changes into it at pharmaceutically acceptable salt.The example of this salt comprises those and organic acid such as toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, oxalic acid, the dimethylene Whitfield's ointment, methylsulphonic acid, ethionic acid, acetate, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, amygdalic acid, styracin, aspartic acid, stearic acid, Palmiticacid, methylene-succinic acid, oxyacetic acid, L-glutamic acid and Phenylsulfonic acid or with the mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, the salt that phosphoric acid and nitric acid form.
The acid-adducting salt of described compound can prepare by methods known in the art.Described alkali can with the acid-respons of calculated amount in the miscible solvent of water such as ethanol or the ketone, and concentrate with cooling after separate excessive acid-respons perhaps and in water immiscible solvent such as ester, methylene dichloride or toluene, and the spontaneous separation of described salt.
The detailed description of the invention
Further specify the present invention by following example, described example can not be thought to limit the scope of the invention.
Embodiment 1
The preparation of citalopram alkali
With 1-(4 '-fluoro phenyl)-1-(3-dimethylaminopropyl)-5-iodobenzene phthalein (7.5g, 18mmol), cuprous cyanide powder (2.4g, 27mmol) and pyridine (5.6g 71mmol) is added in the dimethyl formamide (40ml), with the gained mixture heating up to 140-141 ℃.Further stirred described reaction mixture about 3 hours down at 140-145 ℃.Then, described reaction mixture is cooled to 35 ℃, and dilutes with the cooling mixture of toluene and water.Separate described organic layer, with ammoniacal liquor and water washing.Under vacuum condition, reclaim described toluene fully, make and be the free alkali of buttery.
Embodiment 2
The preparation of citalopram hydrobromate
Toluene (40ml) is added in the free alkali of the above-mentioned citalopram that makes (6.0g), and stirring makes homogeneous solution.Add in this solution enough HBr solution (48%, 3.6g).Then, stirred obtained reaction mixture about 4 hours down, pour out toluene layer at 5-10 ℃.The past new toluene (40ml) that wherein adds, and 5-10 ℃ of further stirring down.Filter isolating solid, and wash with toluene, drying makes citalopram hydrobromate (6.7g, productive rate 93.7%, purity＞98.5% that is recorded by HPLC), is crystalline powder.
Though in conjunction with specific embodiment the present invention has been described, concerning those skilled in the art, some are revised and equivalent embodiments is apparent, and are contained in the scope of the present invention.
Claims (12)
1. the method for preparing citalopram shown in the general formula I,
General formula I
Described method is included in organic bases and exists down, makes general formula III in suitable solvent
General formula III
Shown 5-halo phthalal ether derivant, in the formula, X is a bromine or iodine; With cyanide source reaction, and separate the citalopram shown in the general formula I, as free alkali or be its form at the adduct of pharmaceutically acceptable acid.
2. the described method of claim 1 is characterized in that, described cyanide source is any cyanide ion donor.
3. the described method of claim 2 is characterized in that, described cyanide ion donor is selected from potassium cyanide, sodium cyanide, ammonium cyanide, cuprous cyanide, zinc cyanide, ammonium cyanide, cyaniding tetra-allkylammonium and their mixture.
4. the described method of claim 1 is characterized in that, described suitable solvent is a polar aprotic solvents.
5. the described method of claim 4 is characterized in that, described polar aprotic solvents is selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, N-methylpiperidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene (2H) pyrimidone (DMPU) or their mixture.
6. the described method of claim 5 is characterized in that, described polar aprotic solvents is a dimethyl formamide.
7. the described method of claim 1, it is characterized in that, described organic bases is selected from Trimethylamine, triethylamine, diisopropylamine, picoline, pyridine, pyridine derivate as 2,6-lutidine or 4-methylpyrimidine, quinoline, 1,8-diazonium two ring [5.4.0] 11 carbon-7-alkene (BDU), piperidines, aryl replace amine such as aniline and dicyclohexylamine or their mixture.
8. the described method of claim 7 is characterized in that, described organic bases is pyridine or quinoline.
9. the described method of claim 7 is characterized in that, described organic bases uses with the chemical reaction equivalent or with whenever the excessive use of the about 1-5 molar equivalent of compound shown in the amount general formula III.
10. the described method of claim 1 is characterized in that, described being reflected in about 120-170 ℃ the temperature range carried out.
11. the described method of claim 10 is characterized in that, described being reflected in about 135-145 ℃ the temperature range carried out.
12. the described method of claim 1 is characterized in that described citalopram separates as its hydrobromate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN264/DEL/2001 | 2001-03-09 | ||
| IN264DE2001 | 2001-03-09 |
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| Publication Number | Publication Date |
|---|---|
| CN1496358A true CN1496358A (en) | 2004-05-12 |
| CN1221541C CN1221541C (en) | 2005-10-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028061160A Expired - Fee Related CN1221541C (en) | 2001-03-09 | 2002-03-08 | Process for preparation of citalopram |
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|---|---|
| US (1) | US20050085534A1 (en) |
| EP (1) | EP1370545A4 (en) |
| JP (1) | JP2005500256A (en) |
| CN (1) | CN1221541C (en) |
| BR (1) | BR0207895A (en) |
| CA (1) | CA2439856A1 (en) |
| CZ (1) | CZ20032567A3 (en) |
| HR (1) | HRP20030811A2 (en) |
| HU (1) | HUP0400095A3 (en) |
| PL (1) | PL372133A1 (en) |
| RU (1) | RU2003130073A (en) |
| WO (1) | WO2002072565A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7435838B2 (en) | 2003-12-19 | 2008-10-14 | Hangzhou Minsheng Pharmaceutical Co. Ltd. | Crystalline citalopram diol intermediate alkali |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1526331A (en) * | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
| ITMI991581A1 (en) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | METHOD FOR THE PREPARATION OF CITALOPRAM |
| ITMI991579A1 (en) * | 1999-06-25 | 2001-01-15 | Lundbeck & Co As H | METHOD FOR THE PREPARATION OF CITALOPRAM |
| TR200201166T1 (en) * | 2000-12-22 | 2002-10-21 | H.Lundbecks A/S | Method for the preparation of pure citalopram |
| US7148364B2 (en) * | 2002-01-07 | 2006-12-12 | Sun Pharmaceutical Industries | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile |
-
2002
- 2002-03-08 CN CNB028061160A patent/CN1221541C/en not_active Expired - Fee Related
- 2002-03-08 RU RU2003130073/04A patent/RU2003130073A/en not_active Application Discontinuation
- 2002-03-08 JP JP2002571481A patent/JP2005500256A/en active Pending
- 2002-03-08 WO PCT/IB2002/000690 patent/WO2002072565A1/en active Search and Examination
- 2002-03-08 US US10/469,329 patent/US20050085534A1/en not_active Abandoned
- 2002-03-08 HU HU0400095A patent/HUP0400095A3/en unknown
- 2002-03-08 BR BR0207895-3A patent/BR0207895A/en not_active IP Right Cessation
- 2002-03-08 CA CA002439856A patent/CA2439856A1/en not_active Abandoned
- 2002-03-08 PL PL02372133A patent/PL372133A1/en not_active Application Discontinuation
- 2002-03-08 EP EP02702634A patent/EP1370545A4/en not_active Withdrawn
- 2002-03-08 CZ CZ20032567A patent/CZ20032567A3/en unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7435838B2 (en) | 2003-12-19 | 2008-10-14 | Hangzhou Minsheng Pharmaceutical Co. Ltd. | Crystalline citalopram diol intermediate alkali |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2003130073A (en) | 2005-04-10 |
| HUP0400095A2 (en) | 2004-04-28 |
| CA2439856A1 (en) | 2002-09-19 |
| HRP20030811A2 (en) | 2005-08-31 |
| EP1370545A4 (en) | 2005-03-16 |
| WO2002072565A1 (en) | 2002-09-19 |
| JP2005500256A (en) | 2005-01-06 |
| BR0207895A (en) | 2004-12-28 |
| PL372133A1 (en) | 2005-07-11 |
| CZ20032567A3 (en) | 2004-04-14 |
| US20050085534A1 (en) | 2005-04-21 |
| HUP0400095A3 (en) | 2005-10-28 |
| CN1221541C (en) | 2005-10-05 |
| EP1370545A1 (en) | 2003-12-17 |
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